Various central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include the 5-HT1 family (e.g. 5-HTIA), the 5-HT2 family (e.g. 5-HT2A), 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Lower levels of 5-HT6 receptor mRNA were seen in the granular layer of the cerebellum, several diencephalic nuclei, amygdala and in the cortex. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues. The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Therefore, 5-HT6 receptor ligands are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, attention deficit disorder, migraine, cognitive memory enhancement (e.g. for the treatment of Alzheimer""s disease), sleep disorders, feeding disorders (e.g. anorexia and bulimia), panic attacks, withdrawal from drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines), schizophrenia, or the like; or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a compound of formula 
wherein
W is SO2, CO, CONH, CSNH or (CH2)x;
X is O, SOy or NR13;
Y is CR14 or N;
Z is CR15 or N with the proviso that when Y is N then Z must be CR15;
m and x are each independently 0 or an integer of 1, 2 or 3;
n and p are each independently an integer of 1, 2 or 3;
R1 is halogen, CN, OR16, CO2R17, CONR18R19, CNR20NR21R22, SO2NR23R24, SOwR25, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
R2, R3, R5, R6, R7, R8, R9, R10 and R11 are each independently H or an optionally substituted C1-C6alkyl group;
R4 is H, CNR26NR27R28 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R12 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
y and w are each 0 or an integer of 1 or 2;
R13 is H or a C1-C6alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R14 and R15 are each independently H, halogen or a C1-C6alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
R16 is H, COR29 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
R17 and R29 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R18, R19, R20, R21 R22, R26, R27, and R28 are each independently H or an optionally substituted C1-C6alkyl group;
R23 and R24 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted; and
R25 is an optionally substituted C1-C6alkyl, aryl, or heteroaryl group; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
The present invention further provides a method for the preparation of compounds of formula I and a compound useful therefor.
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that heterocyclylalkoxy-, -thioxy- or -aminobenzazole derivatives of formula I demonstrate 5-HT6 affinity. Advantageously, said benzazole derivatives may be used as effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides heterocyclylalkoxy-, -alkylthio- or -alkylaminobenzazole derivatives of formula I 
wherein
W is SO2 CO, CONH, CSNH or (CH2)x;
X is O, SOy or NR13;
Y is CR14 or N;
Z is CR15 or N with the proviso that when Y is N then Z must be CR15;
m and x are each independently 0 or an integer of 1, 2 or 3;
n and p are each independently an integer of 1, 2 or 3;
R1 is halogen, CN, OR16, CO2R17, CONR18R19, CNR20NR21R22, SO2NR23R24, SOwR25, or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl group each optionally substituted;
R2, R3, R5, R6, R7, R8, R9, R10, and R11 are each independently H or an optionally substituted C1-C6alkyl group;
R4 is H, CNR26NR27, R28 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R12 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
y and w are each 0 or an integer of 1 or 2;
R13 is H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R14 and R15 are each independently H, halogen or a C1-C6alkyl, aryl, heteroaryl or C1-C6alkoxy group each optionally substituted;
R16 is H, COR29 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, aryl or heteroaryl group each optionally substituted;
R17 and R29 are each independently H or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R18, R19, R20, R21 R22, R26, R27 and R28 are each independently H or an optionally substituted C1-C6alkyl group;
R23 and R24 are each independently H or a C1-C6alkyl, aryl or heteroaryl group each optionally substituted; and
R25 is an optionally substituted C1-C6alkyl, aryl, or heteroaryl group; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F and the term cycloheteroalkyl designates a C5-C7cycloalkyl ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein X1 is NR, O or S. 
Similarly, as used in the specification and claims, the term heteroaryl designates a 5- to 10-membered aromatic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. The term haloalkyl as used herein designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different and the term haloalkoxy as used herein designates an OCnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different.
In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C7cycloalkyl, cycloheteroalkyl, phenyl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulfonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, 0-3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Compounds of the invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds of Formula I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an opticaly active form.
Preferred compounds of the invention are those compounds of formula I wherein W is SO2 or CO. Also preferred are those compounds of formula I wherein X is O. Another group of preferred compounds of the invention are those compounds of formula I wherein Y is CR14. Further preferred compounds of the invention are those compounds of formula I wherein R12 is an aryl or heteroaryl group each optionally substituted; and n is 1.
More preferred compounds of the invention are those compounds of formula I wherein W is SO2; X is O; and n is 1. Another group of more preferred compounds of the invention are those compounds of formula I wherein W is SO2; X is O; Y is CR14; n is 1; and p is 1.
Among the preferred compounds of the invention are:
1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-[(2-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-[(3-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-[(4-fluorophenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-[(3,4-dimethoxyphenyl)sulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indole;
4-({4-[2S)-pyrrolidin-2-ylmethoxy]-1H-indole-1-yl}sulfonyl)aniline;
1-(phenylsulfonyl)-4-[(2R)-pyrrolidin-2-ylmethoxy]-1H-indole;
1-(phenylsulfonyl)-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;
8-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)quinoline;
1-[(2-chlorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;
1-[(2-fluorophenyl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;
1-[(5-chlorothien-2-yl)sulfonyl]-4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazole;
4-({4-[(2S)-pyrrolidin-2-ylmethoxy}-1H-indazol-1-yl}sulfonyl)aniline;
2-chloro-4-({4-[(2S)-pyrrolidin-2-ylmethoxy]-1H-indazol-1-yl}sulfonyl)aniline;
1-(phenylsulfonyl)-4-(piperidin-2-ylmethoxy)-1H-indole;
4-{[4-(piperidin-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;
1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;
1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;
1-[(3-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indole;
1-[(2-fluorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;
1-[(2-chlorophenyl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;
1-[(5-chlorothien-2-yl)sulfonyl]-4-(piperidin-2-ylmethoxy)-1H-indazole;
4-(azepan-2-ylmethoxy)-1-(phenylsulfonyl)-1H-indole;
4-{[4-(azepan-2-ylmethoxy)-1H-indol-1-yl]sulfonyl}aniline;
4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indole;
4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indole;
4-(azepan-2-ylmethoxy)-1-[(3-fluorophenyl)sulfonyl]-1H-indole;
4-(azepan-2-ylmethoxy)-1-[(2-fluorophenyl)sulfonyl]-1H-indazole;
4-(azepan-2-ylmethoxy)-1-[(2-chlorophenyl)sulfonyl]-1H-indazole;
4-(azepan-2-ylmethoxy)-1-[(5-chlorothien-2-yl)sulfonyl]-1H-indazole;
1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indole;
1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indole;
1-(phenylsulfonyl)-5-(pyrrolidin-2-ylmethoxy)-1H-indazole;
1-(phenylsulfonyl)-6-(pyrrolidin-2-ylmethoxy)-1H-indazole; or
the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard separation and isolation techniques. For example, compounds of formula I wherein W is SO2; X is O; Y is CR13; Z is CR14; and R4 and R11 are H (Ia) may be prepared by reacting an hydroxyindole of formula II with an N-protected-2-methoxyheterocycle of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the corresponding indol-4-yloxyalkylheterocycle of formula IV. Subsequent sulfonylation and deprotection of the formula IV compound gives the desired formula Ia product. The reaction sequence is illustrated in flow diagram I wherein P represents a protecting group. 
Commonly used protecting groups include t-butyl-carboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.
Compounds of formula I wherein W is SO2; X is O; Y is CH; Z is N and R4 and R11 are H (Ib) may be prepared by reacting a nitromethylphenol of formula V with an N-protected-2-alkoxyheterocyclic compound of formula III in the presence of triphenylphosphine and diethyl azodicarboxylate to give the corresponding heterocyclylalkoxybenzene of formula VI, reducing the nitro group of the formula VI compound, for example via catalytic hydrogenation, to give the amine of formula VII and reacting the formula VII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the heterocyclyalkoxyindazole of formula VIII. Sulfonylation and deprotection of said formula VIII compound gives the desired compound of formula Ib wherein R4 is H. Subsequent reaction of the formula Ib compound with a suitable alkylating reagent such as an alkyl or aralkyl halide, R4-Hal, gives those compounds of formula Ibxe2x80x2 wherein R4 is other than H. The reaction sequence is shown in flow diagram II wherein P is a protecting group and Hal is Cl, Br or I. 
Compounds of formula I wherein W is SO2; X is NH; Y is CH; Z is N; and R4 and R11 are H (Ic) may be prepared by the reductive amination of an N-protected carbonylalkylheterocyclic compound of formula X with a nitromethylaniline compound of formula IX to give the compound of formula XI, reducing the nitro group to give the amine of formula XII and reacting the formula XII amine with isoamylnitrite in the presence of potassium acetate and acetic anhydride to give the heterocyclylalkylamino-indazole of formula XIII. Subsequent sulfonylation and deprotection as described hereinabove give the desired compound of formula Ic. The reaction sequence is shown in flow diagram III. 
Similarly, compounds of formula I wherein W is SO2; X is NH; Y is CR13; Z is CR14; and R4 and R11 are H (Id) may be prepared by the reductive amination of the formula X carboxyaldehyde with an aminoindole of formula XIV to give the compound of formula XV. Subsequent sulfonylation and deprotection gives the desired product of formula Id. The reaction sequence is shown in flow diagram IV. 
Compounds of formula I wherein X is S and W is SO2 may be prepared by employing the appropriate indolylthiol or thiophenol and utilizing the reactions shown in flow diagrams I and II, respectively.
Compounds of formula I wherein W is CO may be prepared by reacting the benzazole precursor, for example a compound of formula IV, VIII, XIII or XV with the appropriate isocyanate, carbonyl halide or carbamoyl halide in the presence of a base. Similarly, compounds of formula I wherein W is (CH2)x and x is an integer of 1, 2 or 3 may be prepared by reacting the appropriately substituted alkylhalide with a compound of formula IV, VIII, XIII or XV in the presence of a base. Compounds of formula I wherein W is (CH2)x and x is 0 may be prepared via a palladium-catalyzed N-arylation such as that descrited by D. W. Old et al, Organic Letters, 2000 (2), pp 1403-1406. Using these and other conventional methods, compounds of formula I may be prepared from readily available starting materials.
Advantageously, the present invention provides a compound of formula XVI 
wherein X, Y, Z, m, n, p, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 are as defined for formula I. Compounds of formula XVI are useful in the preparation of the therapeutic agents of formula I described hereinabove. Accordingly, the present invention also provides a method for the preparation of a compound of formula I wherein W is SO2 (Ie) which comprises reacting a formula XVI compound with a sulfonyl chloride, R12SO2Cl, wherein R12 is as defined for formula I in the presence of a base optionally in the presence of a solvent. The reaction is shown in flow diagram V. 
Bases suitable for use in the method of invention are strong bases such as NaH, KOt-Bu, or any conventional base capable of removing a proton from a basic indole or benzazole nitrogen atom.
Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders, for example, Alzheimer""s disease, Parkinson""s disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, migraine, sleep disorders, feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawl from drug abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are provided by administering the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.
Unless otherwise stated, all parts are parts by weight. The term NMR designates nuclear magnetic resonance. The terms THF and EtOAc designate tetrahydrofuran and ethyl acetate, respectively.